Pharmacodynamic phase, defined

Define the terms pharmacokinetic phase and pharmacodynamic phase in the context of drug action. List the main general factors that affect these phases. 

Human pharmacology (Phase I) Assess tolerance Define/describe pharmacokinetics and pharmacodynamics Explore drug metabolism and drug interactions Estimate activity Dose-tolerance studies Single and multiple dose PK and/or PD studies Drug interaction studies... 

The measurement of pharmacodynamics (PD) parameters in phase 1 studies can be very informative. First of all it may help to define the starting dose for subsequent studies in patients. It may also help to build a PK/PD model, which can be used as a framework for further development. 

The Phase I study was designed as a randomized, double-blind, placebo-controlled, single ascending dose study to evaluate the pharmacokinetics and pharmacodynamics of the new ERA. Cohorts of nine subjects with baseline hemoglobin levels less than 14.5 g/dl were randomized to receive ERA treatment (N= 6) or matched placebo (N= 3) at each dose level. The various dose levels considered in this study were lx, 3x, lOx, 30x, lOOx, and 300x. The objective of the study was to identify the pharmacological effective dose (PED), defined as the dose level where four or more treated subjects achieved more than 1 g/dl increase from baseline in hemoglobin within 28 days. 

Pharmacokinetic/pharmacodynamic modeling plays an important role during the NDA submission and review phase by integrating information from the pre-clinical and development phases. Existence of a well-defined PK/PD model furthermore enables the reviewer to perform PK/PD simulations for various scenarios. This ability helps the reviewer gain a deeper understanding of the compound and provides a quantitative basis for dose selection. Thus, PK/PD modeling can facilitate the NDA review process and help resolve regulatory issues. ... 

A DNA vaccine candidate that has successfully passed all preclinical hurdles needs to be tested clinically by a three-phased scheme as outlined in Chapter 4. As defined by a European Council directive, a clinical trial means ... any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of. .. investigational medicinal product(s), and/or to identify any adverse reactions. .. and/or to study absorption, distribution. 

Regardless of the techniques used, the goals should be to characterize the pharmacokinetics in the patient population, and to quantify the dose-concentration-effect relationship. Phase Ila studies allow the first characterization of pharmacokinetics in patients, but opportunities for pharmacodynamic evalnation or phar-macokinetic/pharmacodynamic modeling may be more limited than in Phase 11b. With Phase Ilb data over several doses, it may be possible to define this relationship, or at least obtain estimates of the lowest useful concentration and the concentration beyond which additional response is not anticipated. Since Phase 11 patient popnla-tions tend to be larger and more diverse than the healthy volunteers nsed in Phase I studies, there are further opportunities to help identify sources of interindividual variability in pharmacokinetics and pharmacodynamics. 

FIGURE 1 Pharmacokinetics versus pharmacodynamics. Pharmacokinetics deals with the phases of drug absorption, drug distribution, and drug elimination. Pharmacodynamics defines the biological effect of a drug at a site of action. 

---